Method for treating and/or preventing retinal diseases with substained release corticosteroids

ABSTRACT

The present invention relates to a method for administering a corticosteroid to a posterior segment of an eye. In the method, a sustained release device is implanted to deliver the corticosteroid to the eye. The aqueous corticosteroid concentration remains less than vitreous corticosteroid concentration during release of the corticosteroid from the device.

FIELD OF THE INVENTION

[0001] The present invention relates to the field of controlledpharmaceutical delivery, particularly to corticosteroids.

BACKGROUND OF THE INVENTION

[0002] Compounds classified as corticosteroids, such as triamcinolone,can effectively treat some forms of neovascularization such as cornealneovasularization. In general, corticosteroids have been unsuccessful intreating neovscularization of the posterior segment. In many patients,these compounds cause undesirable side effects. These adverse affectsinclude elevations in intraocular pressure and the formation of, oracceleration of, the development of cataracts. Elevations in intraocularpressure are of particular concern in patients who are already sufferingfrom elevated intraocular pressure, such as glaucoma patients. Moreover,a risk exists that the use of corticosteroids in patients with normalintraocular pressure will cause elevations in pressure that result indamage to ocular tissue. Since therapy with corticosteroids isfrequently long term, i.e., several days or more, a potential exists forsignificant damage to ocular tissue as a result of prolonged elevationsin intraocular pressure attributable to that therapy.

[0003] One approach to solving the foregoing problems has been to searchfor specific compounds which are effective in treatingneovascularization without elevating intraocular pressure. Anotherapproach has been to administer corticosteroids in conjunction withanother drug to “block” or reduce the IOP elevating effects of thecorticosteroids or to treat IOP elevation separately with another drug.A further approach has been to intravitreally inject corticosteroids totreat ocular neovascularization.

[0004] There exists a need for an improved method for treating and/orpreventing retinal diseases with corticosteroids.

DISCLOSURE OF THE INVENTION

[0005] An object of the present invention is to provide a method fortreating and/or preventing ocular diseases which have neovascularizationas a component with corticosteroids without the associated adverse sideeffects.

[0006] Additional objects, advantages and other features of theinvention will be set forth in the description which follows and in partwill become apparent to those having ordinary skill in the art uponexamination of the following or may be learned from the practice of theinvention. The objects and advantages of the invention may be realizedand obtained as particularly pointed out in the appended claims.

[0007] According to the present invention, the foregoing and otherobjects are achieved in part by a method for administering acorticosteroid to a posterior segment of an eye, the method comprisingthe step of:

[0008] implanting a sustained release device to deliver thecorticosteroid to the vitreous of the eye wherein aqueous corticosteroidconcentration is less than vitreous corticosteroid concentration duringrelease.

[0009] In accordance with the present invention, the foregoing and otheradvantages are also achieved in part by an implantable, sustainedrelease device for administering a corticosteroid to a posterior segmentof an eye, the device comprising:

[0010] a corticosteroid, wherein the device is configured to providesustained release of the corticosteroid to the vitreous of the eye suchthat aqueous corticosteroid concentration remains less than vitreouscorticosteroid concentration during the release.

[0011] Additional objects and advantages of the present invention willbecome readily apparent to those skilled in this art from the followingdetailed description, wherein embodiments of the invention are describedsimply by way of illustrating of the best mode contemplated in carryingout the invention. As will be realized, the invention is capable ofother and different embodiments, and its several details are capable ofmodifications in various obvious respects, all without departing fromthe invention. Accordingly, the drawings and description are to beregarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF DRAWINGS

[0012]FIG. 1 shows the sustained release profile of a 2 mg fluocinoloneacetonide implant in buffer.

[0013]FIG. 2. shows the vitreous and aqueous levels of fluocinoloneacetonide after implantation of a sustained release device.

DESCRIPTION OF THE INVENTION

[0014] The present invention provides a method for delivering atherapeutic amount of a corticosteroid to the vitreous of an eye butprevents toxic amounts of the corticosteroid from accumulating in theaqueous. The method comprises the step of implanting a sustained releasedevice comprising a corticosteroid to the posterior segment to deliverthe corticosteroid to the vitreous wherein aqueous corticosteroidconcentration is less than vitreous corticosteroid concentration duringrelease of the corticosteroid.

[0015] The present invention is particularly effective in treatingdiseases of the retina, retinal pigment epithelium (RPE) and choroid.These diseases include, for example, ocular neovascularization, ocularinflammation and retinal degenerations. Specific examples of thesedisease states include diabetic retinopathy, chronic glaucoma, retinaldetachment, sickle cell retinopathy, senile macular degeneration,retinal neovascularization, subretinal neovascularization; rubeosisiritis inflammatory diseases, chronic posterior and pan uveitis,neoplasms, retinoblastoma, pseudoglioma, neovascular glaucoma;neovascularization resulting following a combined vitrectomy andlensectomy, vascular diseases retinal ischemia, choroidal vascularinsufficiency, choroidal thrombosis, neovascularization of the opticnerve, diabetic macular edema, cystoid macular edema, macular edema,retinitis pigmentosa, retinal vein occlusion, proliferativevitreoretinopathy, angioid streak, and retinal artery occlusion, and,neovascularization due to penetration of the eye or ocular injury.

[0016] Examples of corticosteroids useful in the present inventioninclude, for example, triamcinolone, dexamethasone, fluocinolone,cortisone, prednisolone, flumetholone, and derivatives thereof.

[0017] By “sustained release device” it is meant a device that releasesdrug over an extended period of time in a controlled fashion. Examplesof sustained release devices useful in the present invention may befound in, for example, U.S. Pat. No. 5,378,475 and U.S. Pat. No.5,773,019, and U.S. Ser. No. 08/919,221 filed on Aug. 28, 1997.

[0018] By “vitreous” of the eye, it is meant the vitreous or vitrealcavity of the eye. By “aqueous” of the eye, it is meant the aqueoushumor of the eye.

[0019] In the present invention, a sustained release device is implantedinto the eye such that it delivers corticosteroid to the posteriorsegment of the eye. In a preferred embodiment, the sustained releasedevice is implanted intravitreally. However, the device may also beimplanted in the choroidal space, sub-retinally, or in the sclera. Thesemethods of administration and techniques for their preparation are wellknown by those of ordinary skill in the art. Methods of administrationand techniques for their preparation are set forth in Remington'sPharmaceutical Sciences.

[0020] The aqueous corticosteroid concentration remains less than thevitreous corticosteroid concentration for substantially the lifetime ofthe sustained release device. Thus, during release of thecorticosteroid, the aqueous corticosteroid concentration is about 0.002μg/ml to about 0.01 μg/ml, such as from about 0.01 μg/ml to about 0.05μg/ml. Preferably, the aqueous corticosteroid concentration is less thanabout 0.05 μg/ml.

[0021] Is contrast, during release of the corticosteroid, the vitreouscorticosteroid concentration remains therapeutic, that is, less thanabout 10 μg/ml. The exact desired concentration depends upon the diseaseand therapeutic index of the drug.

[0022] The sustained release device useful in the present invention isany device which can be implanted to deliver corticosteroid to thevitreous of the eye and can release a corticosteroid for a sustainedperiod of time, that is, for about 1 month to about 20 years, such asfrom about 6 months to about 5 years.

[0023] The sustained release device can be prepared to release thecorticosteroid by pseudo zero order kinetics with a mean release rate ofabout 1 μg/day to about 50 μg/day, such as, about 1 μg/day to about 10μg/day.

[0024] The following non-limiting examples are given by way ofillustration only.

EXAMPLE 1

[0025] Sustained release fluocinolone acetonide devices were implantedinto the vitreous of 4 rabbits while animals in the control groupreceived a sham operation. After implantation, all rabbits received asub-retinal injection of gelatin microspheres releasing basic fibroblastgrowth factor. All control animals developed neovascularization while ¾of the implant group showed no evidence of neovascularization. Noanimals showed any indication of ocular or systemic steroid-inducedtoxicity.

EXAMPLE 2

[0026] Animals received intravitreal fluocinolone acetonide implants andwere sacrificed at 1 month, 4 months, and 11 months. Samples of thevitreous and aqueous were collected for analysis by HPLC. Analysis wasperformed using a fully automated Hitachi HPLC system. The mobile phasewas 40% acetonitrile buffered to a pH of 4.0. The flow rate was 1.0ml/min with an Axxion C-18 column (25 cm×4 mm×5 μm) and UV detection at238 nm. Intravitreal levels were found to be relatively constantthroughout the study (0.1-0.2 μg/ml) while no steroid was detected inthe aqueous humor (limit of detection 0.02 μg/ml).

Detailed Description of the Drawings

[0027]FIG. 1 shows the sustained release profile of a 2 mg flucinoloneacetonide implant in buffer over 100 days. The mean release rate was2.1+/−0.26 μg/day.

[0028]FIG. 2 shows the vitreous and aqueous levels of fluocinoloneacetonide after implantation of a sustained release device. Animals weresacrificed at 4 weeks, 20 weeks, and 1 year. FIG. 2 shows thattherapeutic levels are maintained in the vitreous while drug levels inthe aqueous humor were below the detection limit of the assay.

[0029] In the previous descriptions, numerous specific details are setforth, such as specific materials, structures, chemicals, processes,etc., in order to provide a better understanding of the presentinvention. However, the present invention can be practiced withoutresorting to the details specifically set forth. In other instances,well-known processing structures have not been described in detail inorder not to unnecessarily obscure the present invention.

[0030] Only the preferred embodiment of the invention and but a fewexamples of its versatility are shown and described in the presentdisclosure. It is to be understood that the present invention is capableof use in various other combinations and environments and is capable ofchanges or modifications within the scope of the inventive concept asexpressed herein. All patents, patent applications and publication citedherein are incorporated by reference in their entirety.

What is claimed is:
 1. A method for administering a corticosteroid to a posterior segment of an eye, the method comprising the step of: implanting a sustained release device to deliver the corticosteroid to the vitreous of the eye and wherein aqueous corticosteroid concentration is less than vitreous corticosteroid concentration during release.
 2. A method according to claim 1, wherein aqueous corticosteroid concentration is about 0.002 μg/ml to about 0.01 μg/ml.
 3. A method according to claim 2, wherein aqueous corticosteroid concentration is about 0.01 μg/ml to about 0.05 μg/ml.
 4. A method according to claim 1, wherein aqueous corticosteroid concentration is non-toxic and is less than 0.05 μg/ml.
 5. A method according to claim 1, wherein the device releases corticosteroid for about 1 month to about 10 years.
 6. A method according to claim 5, wherein the device releases corticosteroid for about 6 months to about 5 years
 7. A method according to claim 1, wherein the vitreous corticosteroid concentration is therapeutic.
 8. A method according to claim 1, wherein the vitreous corticosteroid concentration is less than about 10 μg/ml.
 9. A method according to claim 1, wherein the corticosteroid is selected from the group consisting of triamcinolone, dexamethasone, fluocinolone, cortisone, prednisolone, flumetholone, and derivatives thereof.
 10. A method according to claim 1, comprising intravitreally implanting the sustained release device.
 11. A method according to claim 1, wherein a disease state to be treated is selected from the group consisting of ocular neovascularization, ocular inflammation and retinal degeneration.
 12. A method according to claim 1, wherein the sustained release device releases the corticosteroid with pseudo zero order kinetics.
 13. A method according to claim 1, wherein the sustained release device has a mean release rate of about 1 μg/day to about 50 μg/day of corticosteroid.
 14. A method according to claim 13, wherein sustained release device has a mean release rate of about 1 μg/day to about 10 μg/day of corticosteroid.
 15. A method according to claim 1, wherein the sustained release device releases only one drug.
 16. An implantable, sustained release device for administering a corticosteroid to a posterior segment of an eye, the device comprising: a corticosteroid, wherein the device is configured to provide sustained release of the corticosteroid to the vitreous of the eye such that aqueous corticosteroid concentration remains less than vitreous corticosteroid concentration during the release. 